1. Field of the Invention
The present invention is directed to a method for reducing intraocular pressure in warm-blooded animals. More specifically, the present invention is directed to reducing intraocular pressure in warm-blooded animals through the use of a select group of "keto" sympathomimetic amines.
2. Description of the Prior Art
Ocular hypertension is associated with glaucoma, a disease of the eye characterized by a progressive increase in intraocular pressure which occurs over a prolonged period of time and which, if untreated, continues until the optic nerve is deteriorated to such an extent that blindness occurs. The goal in the treatment of glaucoma is to reduce the intraocular pressure sufficiently to prevent damage to the optic nerve. The adrenergic amine, epinephrine, when applied topically to the eye, is a widely used treatment for glaucoma. Miotics, which include certain parasympathomimetics such as pilocarpine and cholinesterase inhibitors such as physostigmine, are also widely employed topically. However, due to the increase in side effects observed with existing drugs, their partial application in the treatment of glaucoma is questionnable. For instance, common undesirable side effects induced by the miotic drugs include twitching of the eyelids, browache, headache, extensive ocular pain, conjunctival congestion, etc. Localized allergy occasionally develops as well. Absorption of the topically applied drug occasionally causes systemic effects also. This is particularly true with the cholinesterase inhibitors which may cause salivation, sweating, nausea, vomiting, bradycardia, hypotension, etc., and with adrenergic (sympathomimetic) agents which may cause tachycardia, hypertension, headaches, sweating, tremors, etc. The alpha-adrenergic stimulating action of epinephrine, for instance, frequently causes mydriasis and sometimes, retinal maculophehy during prolonged usage.
Isoproterenol, an adrenergic agent, whose action differs from epinephrine in that it is considered almost exclusively a beta-adrenergic stimulator, has been evaluated by Ross and Drance, Arch. Ophthal., 83, 39-43 (1970), in patients suffering from ocular hypertension. Satisfactory reduction in intraocular pressure as a result of ocular installation of a 5% isoproterenol hydrochloride solution was obtained. However, concomitant side effects of a serious nature were also observed which prohibited the continued practical use of this drug in the treatment of glaucoma. Among side effects associated with the administration of isoproterenol for reduction of intraocular pressure were marked and dangerous tachycardia of up to 100-150 beats per minute as well as palpitations, a nervous feeling, and weakness.
A clinical study designed to determine the effect of diverse sympathomimetic agents on ocular tension has also been reported by R. Weekers, et al., American Journal of Ophthamology, 40, 666-672 (1955). Included in the study were such diverse sympathomimetic amines as adrenalone (the corresponding ketone derivative of adrenalin) and the dextrorotatory (d) and levorotatory (l) optical isomers of adrenalin (epinephrine). The study established that l-adrenalin (a strong sympathomimetic agent) lowered ocular tension, whereas the corresponding ketone derivative, adrenalone and d-adrenalin (agents having only minimal sympathomimetic activity) do not. As a result of these findings, R. Weekers, et al. concluded that reduced ocular tension results from sympathetic stimulation.
In addition to the foregoing, U.S. Pat. Nos. 3,809,714, 3,839,584 and 3,868,461 and 3,959,485, owned by the present assignee of record, all disclose the use of chemically modified sympathomimetic amines in the treatment of glaucoma and other ailments receptive to sympathomimetic amine activity. Specifically, the dipivaloxy derivatives of epinephrine and isoproterenol are disclosed.
U.S. Pat. No. 3,922,348 discloses successful treatment of intraocular hypertension (glaucoma) with a compound designated as 3,4-dihydroxy-2-(isopropylamino) acetophenone, the corresponding ketone derivative of isoproterenol. A review of this reference reveals that the patentee employs rather excessive concentrations (3%) of the active compound to achieve reduction of intraocular pressure. See, Table I. Additionally, this compound is highly unstable and thus limited in terms of shelf-life.